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Selective inhibitors to improve CPT-11 therapy

Selective inhibitors to improve CPT-11 therapy
选择性抑制剂改善 CPT-11 治疗
批准号:
8458610
负责人:
PHILIP M POTTER
金额:
$29.55万
依托单位国家:
美国
项目类别:
财政年份:
2005
资助国家:
美国
项目状态:
已结题
起止时间:
2005-05-01 至 2015-04-30

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项目成果

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中文摘要
翻译
摘要 CPT-11是一种基于喜树碱的高效抗癌药物,目前已被批准用于治疗 结肠癌。这种化合物是一种前药,被羧酸酯酶激活产生SN-38,一种有效的 拓扑异构酶I中毒。CPT-11的剂量限制毒性是发生48-96小时的迟发性腹泻 在行政管理之后。这被认为部分是由于CPT-11的直接激活引起的,CPT-11分泌在 胆汁,由一种人体肠道羧酸酯酶(CE)产生,这种酶在小肠中高度表达。我们 假设通过抑制这种酶,减少的SN-38将产生于肠道中的药物水解物, 从而降低与CPT-11治疗相关的毒性。因此,此应用程序的目标是 开发可用于减轻CPT-11相关毒性的选择性CE抑制剂 行政管理。基于典型化合物联苯的高效、无毒的小分子缓蚀剂 ,我们建议开发这些药物用于抑制人类肠道CE (希斯)。核磁共振、X射线结晶学、药物化学、定量构效关系、生化和活体方法都将是 用于验证合适的化合物的有效性 本申请的具体目的是:1)确定苯并苯对CE的抑制机制;2) 开发苯并苯的水溶性类似物;3)评估这些化合物的生化和生物学性质 化合物;以及4)评估它们在调节CPT-11诱导的血浆酯酶缺陷的毒性方面的有效性。 Hice在小鼠肠道中表达的小鼠模型。 我们相信,如果成功,这些研究将提供可以改善延迟性腹泻的试剂。 与CPT-11给药有关,并有可能使药物的剂量增加。这很可能 结果提高了抗肿瘤效果,此外,还可以使用这种CPT-11来对抗更多 对这种药物有轻微反应的抗药性恶性肿瘤。
英文摘要
Abstract CPT-11 is a highly effective, camptothecin-based anticancer agent that is currently approved for the treatment of colon cancer. This compound is a prodrug and is activated by carboxylesterases to yield SN-38, a potent topoisomerase I poison. The dose limiting toxicity for CPT-11 is delayed diarrhea that occurs 48-96 hours following administration. This is thought to arise, in part, from direct activation of CPT-11, that is secreted in the bile, by a human intestinal carboxylesterase (CE) that is highly expressed in the small intestine. We hypothesize that by inhibiting this enzyme, reduced SN-38 will be produced from drug hydrolysis in the gut, thereby reducing the toxicity associated with CPT-11 treatment. The goals of this application are therefore to develop selective CE inhibitors that can be used to ameliorate the toxicity associated with CPT-11 administration. Highly potent, non-toxic small molecule inhibitors based upon the prototypical compound benzil have been identified, and we propose to develop these agents for use in inhibition of the human intestinal CE (hiCE). NMR, x-ray crystallography, medicinal chemistry, QSAR, biochemical and in vivo approaches will all be employed to validate the efficacy of suitable compounds The specific aims of this application are: 1) to determine the mechanism of CE inhibition by benzil; 2) to develop water-soluble analogues of benzil; 3) to assess the biochemical and biological properties of these compounds; and 4) assess their efficacy at modulating CPT-11-induced toxicity in a plasma esterase-deficient mouse model where hiCE is expressed in the mouse intestine. We believe that, if successful, these studies will provide reagents that can ameliorate the delayed diarrhea associated with CPT-11 administration, and potentially allow dose intensification of the drug. This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent.
期刊论文(13)
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会议论文
DOI: 10.1021/np300628a
发表时间: 2013-01-25
期刊: Journal of natural products
影响因子: 5.1
作者: [Hatfield MJ, Tsurkan LG, Hyatt JL, Edwards CC, Lemoff A, Jeffries C, Yan B, Potter PM]
通讯作者: Potter PM
DOI: 10.1208/s12248-016-9962-6
发表时间: 2016-11
期刊: The AAPS journal
影响因子: --
作者: [Argikar UA, Potter PM, Hutzler JM, Marathe PH]
通讯作者: Marathe PH
DOI: 10.1517/13543776.2011.586339
发表时间: 2011-08
期刊: Expert opinion on therapeutic patents
影响因子: 6.6
作者: [Hatfield MJ, Potter PM]
通讯作者: Potter PM
DOI: 10.1584/jpestics.r10-06
发表时间: 2010
期刊: Journal of pest science
影响因子: 4.8
作者: [Stoddard SV, Yu X, Potter PM, Wadkins RM]
通讯作者: Wadkins RM
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    Modulation of drug metabolism by Danshen
    Modulation of drug metabolism by Danshen
    Selective Inhibitors to Improve CPT-11 Therapy
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